Two arachidonic acid (AA) metabolites, thromboxane (Tx) A2 and prostacyclin (PGI2), acting through their opposing effects on vasoactivity and platelet aggregation are emerging as potential important controlling influences of vascular homeostasis during shock. We have shown that plasma levels of TxA2 (a potent platelet aggregator and vasconstrictor) are significantly elevated in patients dying of septic shock compared to septic survivors and, nonseptic controls. Likewise our studies with rats have demonstrated marked elevations in plasma TxA2 and PGI2 (an inhibitor of platelet aggregation and vasodilator) in shock induced by either endotoxin or acute intra-abdominal sepsis. The interactions of AA metabolites and their tissue origins in shock remain uncertain, nor is it clear which may be beneficial or deleterious. The goal of our proposed project is to develop new and effective therapeutic interventions based on a better understanding of the role of AA metabolites in septic shock. The specific aims proposed to meet this goal are: (1) To identify cellular and tissue sources of AA metabolites in endotoxic and septic shock. (2) To delineate the potential deleterious or beneficial role of PGI2 in the compensatory and decompensatory stages of endotoxic or septic shock with regard to hemodymanic and hematologic sequelae. (3) To design effective single or conjoint therapy based on a clearer understanding of the patterns of AA metabolism in different forms of experimental sepsis. (4) To evaluate the occurence and specificity of increased AA metabolites in clinical sepsis. The measurement of AA metabolites in patients in septic shock will establish the validity of these experimental approaches and provide an essential data base for eventual rational therapeutic interventions in man. In view of our limited knowledge of the role of AA metabolites in the pathogenesis of sepsis and endotoxemia, the proposed studies will provide essential data in both clinical and experimental areas.